Epidemiological studies in humans have shown a marked decrease in colon and other cancers that correlates with the use of nonsteroidal antiinflammatory drugs (NSAIDs). We have demonstrated that COX-1 and COX-2 deficiencies reduce skin tumorigenesis and believe this reduction is due to altered differentiation. By IHC and western analysis of keratins we have demonstrated differences in terminal differentiation between the wild type and COX null mice. COX2 appears to affect the promotion phase of skin carcinogenesis via its effects on cell replication and differentiation, while COX1, in addition to its effects on differentiation, may influence initiation through modulation of apoptosis in DMBA initiated stem cells.